HU217588B - Acylamino-alkyliden-hydroxy-bisphosphonic acids and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to the general formula PO3H2 | R-NH-A-C-OH (I) | PO3H2 compounds. In the general formula (I), A is - (CH2) n-tube, where n is an integer from 1 to 8; Acid residue of alkynyl acid substituted with alkenylphenyl radical R. The invention also encompasses pharmaceutical compositions for the treatment of tubal and connective tissue disorders comprising the compounds of general formula (I). ŕ

Description

The present invention relates to novel compounds of formula (I). In the general formula (I)

PO ₃ H ₂

I

R-NH-A-C-OH (I)

I

PO ₃ H ₂

- where in the formula

A is - (CH ₂ ) _n - wherein n is an integer from 1 to 8;

R is the acid residue of a C 1-3 alkanecarboxylic acid substituted with (C 1-8 alkyl) phenyl.

Particularly preferred are compounds of formula I wherein R is an acid residue of ibuprofen.

Most preferred are those compounds wherein n is 3 or 5.

In the case where one or more optically active carbon atoms are present in the group R, the present invention also encompasses individual enantiomers as well as mixtures of racemates and diastereoisomers.

The invention also relates to diphosphonic acid salts, esters with phosphonic acid groups and hydroxy groups, provided that these derivatives are pharmaceutically acceptable.

The compounds of formula (I) may be prepared from known antiinflammatory compounds by condensation with known ω-aminoalkylene-1-hydroxy-1,1-diphosphonic acid derivatives, which have an inhibitory effect on bone resorption as well as an anti-urinary action. Compounds having active properties are useful in medicine.

ω-Aminoalkylene-1-hydroxy-1,1-diphosphonic acids are disclosed in Italian Patent Applications IT 1230503 and IT 1229518, and in German Patent Nos. 2,534,391 and 3,540,150.

EP-A 84 822 discloses alkyl-1-hydroxy-1,1-diphosphonic acid derivatives which are condensed via a carbon-carbon bond with the remainder of the anti-inflammatory compounds.

In contrast, the compounds of the invention form an amide bond between the amino group of ω-aminoalkylene hydroxydiphosphonic acid and the carboxyl group of the anti-inflammatory compound.

In contrast to the expected effect, the pharmacological activity of the compounds of formula I is not the same as the expected sum of the independent effect of the two components released in vivo, i.e., it is not a typical prodrug.

Surprisingly, it has been found that the compounds of formula I exhibit a much more potent anti-inflammatory activity than the corresponding known R-OH compounds released in vivo from the compounds. This phenomenon is all the more surprising since the aminoalkyl hydroxydiphosphonic acid component is free from all anti-inflammatory effects.

Compounds of formula (I) are prepared by reacting a compound of formula (II)

PO ₃ H ₂

I

H ₂ NAC-OH (II)

PO ₃ H ₂

wherein A is a compound of formula R-OH as defined above or a reactive derivative thereof such as chloride, anhydride, imidazolide, wherein R is as defined above.

The reaction is conveniently carried out in an aqueous medium in the presence of an alkaline agent, and the R-containing compound is used as a reactive derivative such as an acid chloride.

The compounds of the present invention are useful for treating musculoskeletal disorders because of their beneficial therapeutic effects.

The compounds of the present invention may be formulated into a pharmaceutical composition by combining the active ingredient with suitable carriers and excipients and / or other drugs with a therapeutic effect.

Among the pharmaceutical compositions are those in solid and liquid form for oral administration, preferably sustained release and gastrointestinal resistance; mention is made of injectable formulations, of which the depot type is preferred, and suppositories and topical formulations may be prepared.

The dose of the pharmaceutical composition to be administered will be determined by the type of disease and the condition (age, sex, weight) of the patient being treated, and will be determined by the attending physician. The compositions may also be presented in unit dosage forms, each containing 2 to 500 mg of active ingredient per dose.

The following examples illustrate the present invention.

Example 1 [4- (2-Acetoxybenzoyl) amino-1-hydroxybutylidene] diphosphonic acid

Sodium trihydrogen-4-amino-1-hydroxybutylidene diphosphonate trihydrate (3.18 g, 9.8 mmol) was dissolved in water (30 mL) and sodium hydroxide (1.8 g, 45 mmol), p-dimethyl (100 mg) was added. of aminopyridine and 200 mg of tetrahexylammonium iodide. The resulting mixture was cooled to 0 ° C and a solution of 2-acetoxybenzoic acid chloride (2.03 g, 10.2 mmol) in diethyl ether (10 mL) was added. After stirring for 2 hours at room temperature, the reaction mixture was extracted with ethyl ether and the aqueous solution was acidified with concentrated hydrochloric acid with cooling and stirring. [4- (2-Hydroxybenzoyl) amino-1-hydroxybutylidene] diphosphonic acid precipitated out, was collected by filtration, washed and dried at 70 ° C; the resulting compound2

Acetylated with acetic anhydride gave the title compound.

Melting point:> 150 ° C (dec.).

Analysis calculated for C ₁₃ H ₁₉ NO ₁₀ P ₂ : C, 37.96; H, 4.65; N, 3.40; Found: C, 38.04; H, 4.69; N, 3.45.

The IR and Ή NMR spectral data are in agreement.

Example 2 [6- (2-Acetoxybenzoyl) amino-1-hydroxyhexylidene [diphosphonic acid]

The procedure of Example 1 was followed except that 3.45 g (9.8 mmol) of sodium trihydrogen-6-amino-1-hydroxyhexylidene diphosphonate trihydrate was used as starting material. The precipitate formed in the reaction is [6- (2-hydroxybenzoyl) amino-1-hydroxyhexylidene] diphosphonic acid. The work-up is carried out as in Example 1; The title compound was obtained. Melting point:> 150 ° C (dec.).

Analysis calculated for C ₁₅ H ₂₃ NO ₁₀ P ₂ : C, 41.00; H, 5.27; N, 3.18; Found: C, 40.94; H, 5.23; N, 3.24.

The IR and Ή NMR spectral data are consistent with the expected value.

Example 3 [4- [5- (2,4-Difluoro-phenyl) -2-hydroxy-benzoyl] -amino-1-hydroxy-butylidene] -diphosphonic acid The same procedure as in Example 1, starting with 3.18, was prepared. 5- (2,4-Difluorophenyl) -2-acetoxybenzoic acid chloride (10.2 mmol) was used.

After acidification with concentrated hydrochloric acid, the title compound is precipitated; Characteristics of the compound obtained:

m.p.> 150 ° C (dec.).

Analysis calculated for C ₁₇ H ₁₉ F ₂ NO ₉ P ₂ : C, 42.41; H, 3.97; N, 2.90;

Found: C, 42.36; H, 3.94; N, 2.98.

The IR and Ή-NRM spectral data are consistent with the expected value.

By following the procedures described above, the following compounds can be prepared.

Example 4 [6- [5- (2,4-Difluoro-phenyl) -2-hydroxy-benzoyl] -amino-1-hydroxy-hexylidene] -diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis calculated for C ₁₉ H ₂₃ F ₂ NO ₉ P ₂ : C, 44.80; H, 4.55; N, 2.74; Found: C, 44.85; H, 4.58; N, 2.80.

The IR and Ή NMR spectral data are consistent with the expected value.

Example 5 [4- (4-Isobutylphenyl) acetylamino-1-hydroxybutylidene] diphosphonic acid

Melting point:> 150 ° C (dec.).

Elemental analysis calculated for C ₁₆ H ₂₇ NO ₈ P ₂ :

Found: C, 45.38; H, 6.42; N, 3.30;

Found: C, 45.44; H, 6.47; N, 3.36.

IR and 1 H NMR spectral data are consistent with the expected value.

Example 6 [6- (4-Isobutyl-phenyl) -acetylamino-1-hydroxy-hexylidene] -diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis calculated for C ₁₈ H ₃₁ NO ₈ P ₂ : C, 47.88; H, 6.12; N, 3.10; Found: C, 47.93; H, 6.14; N, 3.18.

Example 7 [4- [2- (4-Isobutylphenyl) propionyl] amino-1-hydroxybutylidene] diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis calculated for C ₁₇ H ₂₉ NO ₈ P ₂ : C, 46.67; H, 6.68; N, 3.20; Found: C, 46.61; H, 6.65; N, 3.27.

The IR and Ή NMR spectral data are consistent with the expected value.

Example 8 [6- [2- (4-Isobutyl-phenyl) -propionyl] -amino-1-hydroxy-hexylidene] -diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis: Calculated for C ₁₉ H ₃₃ NO ₈ P ₂ : C, 49.02; H, 7.14; N, 3.00; Found: C, 48.96; H, 7.09; N, 2.95.

The IR and Ή NMR spectral data are consistent with the expected value.

Example 9 [4- [2- (6-Methoxy-naphthyl) -propionyl] -amino-1-hydroxybutylidene [diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis calculated for C ₁₈ H ₂₅ NO ₉ P ₂ : C, 46.85; H, 5.46; N, 3.03; Found: C, 46.80; H, 5.47; N, 3.00.

The IR and Ή NMR spectral data are consistent with the expected value.

Example 10 [6- [2- (6-Methoxy-naphthyl) -propionyl] -amino-1-hydroxy-hexylidene] -diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis calculated for C ₂₀ H ₂₉ NO ₉ P ₂ : C, 49.07; H, 5.97; N, 2.86.

Found: C, 49.02; H, 5.96; N, 2.90.

Example 11 [4- [1- (4-Chlorobenzoyl) -2-methyl-5-methoxy-2-indolyl] acetylamino-1-hydroxybutylidene] diphosphonic acid

Melting point:> 150 ° C (dec.).

Analysis: Calculated for C ₂₃ H ₂₇ ClN ₂ O ₁₀ P ₂ : C, 46.90; H, 4.62; N, 4.75. Found: C, 46.99; H, 4.66; N, 4.68.

The IR and Ή NMR spectral data are consistent with the expected value.

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Example 12 [6- [1- (4-Chloro-benzoyl) -2-methyl-5-methoxy-2-indolyl] -acetylamino-1-hydroxy-hexylidene] -diphosphonic acid

Melting point:> 150 ° C (dec.).

Elemental Analysis calculated for CjjH jiClINLOLOqPP: C, 48.66; H, 5.06; N, 4.53;

Found: C, H, N.

The IR and ^l H-NMR were consistent with the expected value.

Example 13

Carrageenan edema in rats Materials used: Carrageenan (Control) Carrageenan + Ibuprofen (11 and 5.5 mg / kg) Carrageenan + 8. Example compound (Br-Ax) (25.0 and 12.5 mg / kg) Carrageenan + 7. Example compound (Br-Ab) (25.0 and 12.5 mg / kg)

Note: The dose of ibuprofen is equivalent to the corresponding dose of Br-Ab and Br-Ax.

Animals used for examination:

male S.D. rats weighing 160-180 g

Groups examined:

Control 1 - (carrageenan alone)

2. ibuprofen 11.0 mg / kg

3. ibuprofen 5.5 mg / kg

4. Br-Ab 25.0 mg / kg

5. Br-Ab 12.5 mg / kg

6. Br-Ax 25.0 mg / kg

7. Br-Ax 12.5 mg / kg

Each group is made up of five male animals, each group being designed to have a homogeneous body weight within the group. The animals were treated subcutaneously with the test solutions, which were homogenized in 5% gum arabic; this is sterilized by filtration on an Acrodisc 0.45 μΐ pore filter.

After 1 hour, the animals are mildly anesthetized using 0.1 ml of 1% carrageenin in sterile saline. The solution is stirred using a magnetic stirrer to maintain homogeneity.

Simultaneously, the volumetric volume of the animals is determined by plethysmography, so that the measurements can be repeated several times in the following hours.

one hour after the injection of the carrageenin solution, the volume of the foot is determined (hour 2). 4 and 6 after administration.

after one hour, the measurements are repeated. The percentage protection value is then determined using the following equation:

The volume increase in the treated group was 25 -100 = Α

Volume increase of control volume 100 - A =% protective effect.

Table 1 Protective effect in%

examined compounds Protective effect in% After 2 o'clock Protective effect in% after 4 o'clock Protective effect in% After 6 o'clock Ibuprofen (11.0 mg / kg) 21% 25% 28% Ibuprofen (5.5 mg / kg) 18% 3% 4% Br-Ab (25.0 mg / kg) 68% 57% 38% Br-Ab (12.5 mg / kg) 31% 28% 30% Br-Ax (25.0 mg / kg) 42% 21% 56% Br-Ax (12.5 mg / kg) 41% 36% 48%

The results show that each of the compounds of the invention provides greater protection than ibuprofen; moreover, it has been found that there is a difference in the therapeutic effect of the compounds of the invention depending on the chain length of the substituent A.

Example 14

Male rats weighing about 200 mg were anesthetized with Nembutal, followed by thyroid and parathyroid removal. During the studies, the animals were given thyroxine every other day. Seven days after surgery, the animals are bled by intracardiac puncture and plasma calcium is determined. Animals with a plasma calcium content greater than 2 mmol were excluded from the studies; the others are treated with the test compound and retinoid administered subcutaneously for 3 consecutive days. Twenty-four hours after the last administration, the animals are sacrificed and blood is drawn for further calcium determination.

The results are summarized in Table 2.

Table 2

Changes in retinoid-induced bone calcium loss in rats by Br-Ab and Br-Ax

Compound Increased plasma Ca following administration of retinoid (mmol / l) inhibition (%) control 1.11 ± 0.03 - AHBuBP 0.29 ± 0.2 73.9

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Table 2 (continued)

Compound Increased plasma Ca following administration of retinoid (mmol / l) inhibition (%) Br-Ab 0.62 ± 0.03 44.1 Br-Ax 0.75 ± 0.17 32.4

Note: HBuBP means 4-amino-1-hydroxybutylidene-1,1 diphosphonic acid

Claims (5)

PATIENT INDIVIDUAL POINTS 1. Compounds of Formula I PO ₃ H ₂ I R-NH-A-C-OH (I) I after ₃ h ₂ where the formula is A is - (CH ₂ ) _n - wherein n is an integer from 1 to 8; R is an acid residue of a C 1 -C 3 alkanecarboxylic acid substituted with a C 1 -C 8 alkyl-phenyl group. Compounds according to claim 1, wherein A is as defined in claim 1 and R is an acid residue of ibuprofen. 3. Compounds according to any one of claims 1 to 3, wherein A is - (CH ₂ ) ₅ - or - (CH ₂ ) ₃ - and R is as defined in claim 2. 4. A pharmaceutical composition comprising, as active ingredient, a compound according to any one of claims 1-3. and a pharmaceutically acceptable auxiliary and / or carrier. Pharmaceutical compositions according to claim 4 for the treatment of bone marrow and connective tissue disorders.